We appreciate the interest of Carlson et al in our article on vulvar VX1 as well as their comment about the possible etiologic roles of lymphostasis and HPV. Our 10 vulvar VX cases were all associated with another vulvar condition, mainly LS but also lichen planus (2 cases), vulvar radiodermatitis (1 case), and Paget disease (1 case). Our findings sustain the hypothesis of Zegarelli et al2 that damage to the epithelium —particularly of the DEJ, in our opinion, could trigger the following cascade: (1) entrapment of epithelial cells in the papillary dermis; (2) subsequent degeneration of these cells and lipid formation; (3) engulfment of released lipids by macrophages; and (4) accumulation of foam cells between the rete ridges.

Carlson et al object that this hypothesis does not explain why macrophages accumulate in the papillary dermis. We think that the superficial location of the xanthomatous cells can be explained by the fact that the papillary dermis is the part of the dermis, which is the closest of the damaged epidermis. The poor lymphatic drainage reported by Carlson et al in 14 genital and 4 trunk LS cases could account for the accumulation of macrophages in the papillary dermis. However, to confirm this hypothesis one should demonstrate the following: (1) that all the other conditions associated with mucosal or cutaneous VX are associated with lymphostasis (eg, Paget disease, lichen planus, graft-vs-host disease, discoid lupus erythematosus, pemphigus vulgaris, recessive dystrophic epidermolysis bullosa, lichen planus, epidermal nevus); (2) that lymphostasis is not just an incidental finding related to inflammation, whatever its cause. In addition, if an increased number and dilation of lymphatic vessels is present in most LS cases, these abnormalities cannot alone explain alone the occurrence of VX with LS. Indeed, VX only exceptionally occurs concomitantly with LS.

The second hypothesis advanced by Carlson et al is that the verrucous epidermal hyperplasia that is a hallmark of VX could be related to an HPV infection. This HPV infection may have been facilitated by the lymphostasis, the source of the disrupted immune-cell trafficking and consequently of localized immunosuppression. This interesting assumption is not corroborated either by the pathologic features of VX or by the available virologic data. Indeed, we found that the verrucous hyperplasia of VX had specific, almost pathognomonic, histologic features that differ from those of HPV infections: wedge-shaped parakeratosis forming deep invaginations into the acanthotic epithelium and exhibiting a characteristic orange hue under hematoxylin-eosin stain; and neutrophilic infiltrate at the junction between the superficial parakeratotic layers and the underlying stratum spinulosum. In addition, neither koilocytes nor atypia were observed.

In our retrospective study, no HPV search was performed. However, the data collected from the literature are mainly negative, even though very sensitive methods were used.3 A few cases with a positive HPV search have been reported,4 but these findings could have been incidental: HPV may be present on normal vulvar or oral mucosa in as many as 23.3% of the cases.5